2-(1-di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxyphenyl)acetic acid | 900174-87-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2-(1-di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxyphenyl)acetic acid
• 英文别名: 2-[[1-[Bis[(2-methylpropan-2-yl)oxycarbonyl]amino]isoquinolin-6-yl]amino]-2-(2-fluoro-5-methoxyphenyl)acetic acid
• CAS: 900174-87-0
• 化学式: C₂₈H₃₂FN₃O₇
• 分子量: 541.576
• InChiKey: QLUZMNCWIJNUSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  39
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (R)-methyl (4-(isopropylsulfonyl)-3-(pyrrolidin-2-yl)phenyl)carbamate hydrochloride 、 2-(1-di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxyphenyl)acetic acid 在 盐酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 水 、 乙酸乙酯 为溶剂， 反应 4.0h， 生成 methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate trifluoroacetic acid salt
  参考文献：
  名称：

  Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors

  摘要：

  Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t(1/2) in dog PK studies.

  DOI：

  10.1021/ml400453z
• 作为产物：
  描述：

  6-amino-1-(di-tert-butoxycarbonylamino)isoquinoline 、 乙醛酸 、 2-氟-5-甲氧基苯硼酸 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 0.5h， 以25%的产率得到2-(1-di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxyphenyl)acetic acid
  参考文献：
  名称：

  Phenylglycinamide and pyridylglycinamide derivatives useful as anticoagulants

  摘要：

  本发明提供了式(I)或(IV)的新型苯基甘氨酰衍生物：或其立体异构体、互变异构体、药学上可接受的盐、溶剂合物或前药，其中变量W、W1、Y、Z、R7、R8、R9和R11如本文所定义。这些化合物是选择性因子VIIa的抑制剂，可用作药物。

  公开号：

  US20070003539A1

文献信息

• Phenylglycinamide and pyridylglycinamide derivatives useful as anticoagulants
  申请人：Zhang Xiaojun

  公开号：US20070003539A1

  公开（公告）日：2007-01-04

  The present invention provides novel phenylglycinamide derivatives of Formula (I) or (IV): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the variables W, W 1 , Y, Z, R 7 , R 8 , R 9 , and R 11 are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.

  本发明提供了式(I)或(IV)的新型苯基甘氨酰衍生物：或其立体异构体、互变异构体、药学上可接受的盐、溶剂合物或前药，其中变量W、W1、Y、Z、R7、R8、R9和R11如本文所定义。这些化合物是选择性因子VIIa的抑制剂，可用作药物。
• WO2006/76246
  申请人：——

  公开号：——

  公开（公告）日：——
• US7456195B2
  申请人：——

  公开号：US7456195B2

  公开（公告）日：2008-11-25
• US7622585B2
  申请人：——

  公开号：US7622585B2

  公开（公告）日：2009-11-24
• Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors
  作者：Xiaojun Zhang、Wen Jiang、Swanee Jacutin-Porte、Peter W. Glunz、Yan Zou、Xuhong Cheng、Alexandra H. Nirschl、Nicholas R. Wurtz、Joseph M. Luettgen、Alan R. Rendina、Gang Luo、Timothy M. Harper、Anzhi Wei、Rushith Anumula、Daniel L. Cheney、Robert M. Knabb、Pancras C. Wong、Ruth R. Wexler、E. Scott Priestley

  DOI：10.1021/ml400453z

  日期：2014.2.13

  Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t(1/2) in dog PK studies.